Cardiovascular diseases and disorders remain a leading cause of morbidity and mortality in industrialized countries despite aggressive vascular intervention and a myriad blood pressure- and lipid-lowering agents. Atherosclerosis, manifested by heart disease, stroke, and peripheral vascular disease is characterized by the progressive formation of fatty streaks, stable plaques and unstable or ruptured plaques which trigger clinical complications due to intravascular thrombosis. Over the past decade, however, our understanding of atherogenesis has evolved from one of occlusive lipid accumulation to one of chronic inflammation involving cellular proliferation. (Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med1999; 340: 115-126).
Atherosclerosis is a condition in which fatty material is deposited along the walls of arteries. This fatty material thickens, hardens, and may eventually block the arteries. Atherosclerosis is characterized by thickening and hardening of artery walls wherein fat, cholesterol, and other substances accumulate in the walls of arteries and form “atheromas” or plaques. Eventually, this fatty tissue can erode the wall of the artery, diminish its elasticity (stretchiness) and interfere with blood flow. Plaques can also rupture, causing debris to migrate downstream within an artery. This is a common cause of heart attack and stroke. Clots can also form around the plaque deposits, further interfering with blood flow and posing added danger if they break off and travel to the heart, lungs, or brain.
Atherosclerosis often shows no symptoms until flow within a blood vessel has become seriously compromised. Typical symptoms of atherosclerosis include chest pain when a coronary artery is involved, or leg pain when a leg artery is involved. Sometimes symptoms occur only with exertion. In some people, however, they may occur at rest. Atherosclerosis may not be diagnosed until symptoms develop. Prior to complications, atherosclerosis may be noted by the presence of a “bruit” (a whooshing or blowing sound heard over the artery with a stethoscope). Tests that may be indicative of atherosclerosis (or complications) include, for example, abnormal differences between the blood pressure of the ankle and arm, Doppler study of the affected area, ultrasonic Duplex scanning, CT scan of the affected area, Magnetic resonance arteriography (MRA), arteriography of the affected area, intravascular ultrasound (IVUS) of the affected vessels, cardiac stress testing.
An aneurysm is a bulge in a blood vessel with the potential risk of lethally acute rupture. Typically, the blood vessel balloons to a diameter which is at least 1.5 fold larger than its normal diameter. Abdominal aorta is the most frequent site where aneurysm usually occurs. An aortic aneurysm is an aneurysm in which the aorta increases in diameter to a size at least about 1.5 times the diameter of the normal diameter of the aorta. Abdominal aortic aneurysms are characterized by medial degeneration and involve multiple processes including inflammation, immunologic cell infiltration, proteolysis. Abdominal aortic aneurysms are often, although not necessarily, associated with atherosclerosis, a chronic inflammatory disease consisting of lipid deposits into major plaques within the vessel wall.
Pain in the area of an aneurysm is a common symptom. Imaging techniques, such as X-ray, echocardiography, magnetic resonance imaging (MRI) or computed tomography (CT) scan are the common means for diagnosis. Prevention of life-threatening sudden bursts of the abdominal aorta is essentially limited to prophylactic surgery. However, elective surgery of small aneurysms (greater than two fold dilation, but smaller than 5.5 cm) does not improve survival. Therefore, interventions with drugs that target key pathogenic factors of aneurysm formation would be highly desirable.
There are several current treatments for cardiovascular diseases and disorders including aneurysms and atherosclerosis. Medications may be prescribed to reduce fats and cholesterol in the blood; a low-fat diet, weight loss, and exercise are also usually suggested. Control of high blood pressure is also important. Medications commonly prescribed include cholestyramine, colestipol, nicotinic acid, gemfibrozil, probucol, atorvastatin, lovastatin, and others. Aspirin, ticlopidine, and clopidogrel (inhibitors of platelet clumping) or anti-coagulants may be used to reduce the risk of clot formation. Balloon angioplasty uses a balloon-tipped catheter to flatten plaque and increase the blood flow past the deposits and is used to open the arteries of the heart and other arteries in the body. Another widely used technique is stenting which consists of implanting a small metal device—a stent—inside the artery (usually following angioplasty) to keep the artery open. Recently, stents have been coated with biopharmaceuticals designed to limit the proliferative response to the vascular injury of angioplasty. This proliferative response may cause a failure of response to angioplasty in up to a third of cases.
Surgically removal of deposits (endarterectomy) may be recommended in some cases. A bypass graft is the most invasive procedure, using a normal artery or vein from the patient to create a bridge that bypasses the blocked section of the artery.
Prostaglandins mediate inflammation locally and modulate physiological responses systemically. Nearly all tissues produce prostaglandins and increase production at sites of inflammation. Specifically, arachidonic acid is metabolized to prostaglandin G2 (PGG2) and then to prostaglandin H2 (PGH2) by cyclooxygenase. These moieties are then converted to PGD2, PGE2, PGF2, PGI2, or thromboxane.
Substantial evidence has demonstrated that COX products, such as thromboxane A2 (TxA2) and prostaglandin I2 (PGI2), play active role in atherogenesis and heart disease generally. Low dose aspirin prevents heart attack and stroke by suppressing TxA2. Selective inhibitors of Cox-2 may suppress PGI2 without a concomitant effect on TxA2. Prostaglandin D2 (PGD2), a major COX metabolite, has been implicated as a pro-inflammatory lipid mediator, but also exhibits anti-inflammatory properties. The biological effects of prostaglandin D2 (PGD2) are transduced by at least two 7-transmembrane G-protein coupled receptors, designated DP1 and DP2 (CRTH2). Although evidence has linked these two receptors to vascular biology and platelet function in vitro, the expression and roles of the DP1 and DP2 in the cardiovascular system in vivo and its potential role in cardiovascular disease remains unknown.
Mitogen-activated protein kinase (MAPKs) (also called extracellular signal-regulated kinases or ERKs) are rapidly activated in response to ligand binding by both growth factor receptors that are tyrosine kinases and receptors that are coupled to heterotrimeric guanine nucleotide binding proteins (G proteins) such as the thrombin receptor. The MAPKs appear to integrate multiple intracellular signals transmitted by various second messengers. MAPKs phosphorylate and regulate the activity of enzymes and transcription factors including the EGF receptor, Rsk 90, phospholipase A2, c-Myc, c-Jun and Elk-1/TCF. MAPK pathways have established relevance in transmitting proliferative signals from cell membrane receptors to the nucleus.
There is a need for inhibitors of cardiovascular diseases and disorders, especially aneurysms. Similarly, there is a need for therapeutic methods for preventing and/or treating such cardiovascular diseases and disorders. There is also a need for methods of identifying inhibitors of these cardiovascular diseases and disorders as well as model systems suitable for identifying such inhibitors. A need also exists for novel methods and compositions for detecting and/or diagnosing cardiovascular diseases and disorders, especially aneurysms.